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Authors: Dong Hyun Sinn, Danbee Kang, Eliseo Guallar, Juhee Cho, Geum‐Youn Gwak
Journal: Hepatology (2022)

Dong Hyun Sinn and Danbee Kang contributed equally to this work. We thank Dr. Zhang et al.[1] for their interest in our study.[2] We agree that our study is not sufficient to prove a causal effect of NAFLD on sarcopenia. Participants with and without NAFLD were very different, and multivariate adjustment might not be enough to completely remove confounding. In response to Zhang et al.[1], we further evaluated the association between incident NAFLD as a time‐varying variable and the loss of appendicular skeletal muscle mass among participants without NAFLD at baseline (n = 35,956). Participants who developed NAFLD during follow‐up (N = 9670; 26.9%) had a faster loss of appendicular skeletal muscle mass compared with those without NAFLD throughout follow‐up (5‐year change, −69.3 g; 95% confidence interval, −87.0, −51.7; Table 1), even after adjusting for baseline appendicular skeletal muscle mass. This analysis further supports that NAFLD is a risk factor for sarcopenia. TABLE 1 - Five‐year change in appendicular skeletal mass (in grams) in participants with and without incident NAFLD during follow‐up among participants without NAFLD at baseline (N = 35,956) Incident NAFLD during follow‐up No (N = 26,286) Yes (N = 9670) Overall (N = 35,956) 0.0 (reference) −69.3 (−87.0, −51.7) Age Age < 50 years (N = 20,225) 0.0 (reference) −105.1 (−129.5, −80.8) Age ≥ 50 years (N = 15,731) 0.0 (reference) −47.0 (−72.7, −21.4) p for interaction — 0.05 Sex Male (N = 16,582) 0.0 (reference) −12.9 (−37.6, 11.8) Female (N = 19,374) 0.0 (reference) −173.4 (−198.9, −147.9) p for interaction — 0.17 Note: Adjusted for baseline age, baseline age × time, sex, sex × time, baseline weight, height, height × time, smoking status (never, ever, and missing), alcohol intake (none, light, moderate, and missing), alcohol intake × time, physical activity (<3 times/week, ≥3 times/week and missing), physical activity × time, diabetes, diabetes × time, hypertension, hyperlipidemia, and baseline appendicular skeletal mass. Age, weight, and height were included in the model as restricted cubic splines with four degrees of freedom. When investigating causality in population research, the gold standard is a randomized controlled trial.[3] Although a well‐designed Mendelian randomization (MR) study may provide valid evidence on causality, there are still limitations and assumptions in its application.[3] In addition, the MR analysis cited by Zhang et al. in their letter[4] did not provide a detailed definition of NAFLD.[4] NAFLD is characterized by fat infiltration of the liver in absence of secondary causes for hepatic steatosis, and fat infiltration can be identified by liver biopsy, imaging, or serum biomarkers.[5] In our study, fat infiltration of the liver was identified by abdominal ultrasonography, and it is unclear if the study cited by Zhang et al. is relevant to our analysis. In addition, the relationship between sarcopenia and NAFLD might be bidirectional, with each condition affecting the other. We agree that further studies are needed to establish causality, but our results raise concerns about a possible role of NAFLD in increasing the risk of sarcopenia. AUTHOR CONTRIBUTIONS Conceptualization: Dong Hyun Sinn, Juhee Cho, and Geum‐Youn Gwak. Formal analysis: Danbee Kang, Juhee Cho, and Eliseo Guallar. Writing – original draft: Dong Hyun Sinn and Danbee Kang. Writing – review and editing: Eliseo Guallar, Juhee Cho, and Geum‐Youn Gwak. CONFLICT OF INTEREST Nothing to report.